Nanocomposite particles

ABSTRACT

Nanocomposite particles having good solubility and redispersibility in water are provided. The nanocomposite particles include a sugar material and nanoparticles containing a drug to be delivered and a biodegradable polymer, the sugar material being disaccharide, and a mass ratio of the nanoparticles to the disaccharide being within the range of from 40:60 to 60:40.

TECHNICAL FIELD

The present invention relates to nanocomposite particles includingnanoparticles containing a drug to be delivered, and a sugar material.

RELATED ART

Nanoparticles containing a drug to be delivered have various advantagesin a Drug Delivery System (DDS). For example, in the case ofadministration by injection, nanoparticles have great advantages such asa reduction in adverse side effects by selectively concentrating at theliver, the lung, an inflammatory site, or the like to release the drug.Also, in the case of oral administration, an increase in digestiveabsorption of a physiologically active substance having lowabsorbability can be expected. In the case of transdermaladministration, it is possible to locally administer a physiologicallyactive substance. Further, in the case of directly administeringnanoparticles to the alveoli, the nanoparticles have various advantagessuch as transferring the drug directly to the blood while avoidingcapture by alveolar macrophages.

However, with respect to direct handling of the nanoparticles, there arevarious problems such as adhesion and coagulation, instability, andscattering. Also, in the case of handling the nanoparticles in adispersion liquid state, the dispersion liquid has problems related tostability such as the occurrence of reaggregation. Further, it isgenerally considered that an aerodynamic particle diameter must bewithin the range of from about 1 to about 5 μm for particles that arepulmonarily administered to reach the alveoli, and there is a problemthat nanoparticles having a particle diameter smaller than theabove-specified range are discharged by exhalation without beingdeposited at the alveoli after being taken in by direct inhalation. Inorder to avoid such problems, various nanocomposite particles obtainedby coating nanoparticles with a coating substance and having a particlediameter of microsize have been proposed, but nanocomposite particlescapable of fully solving the above problems have not yet been disclosed.

For example, Patent Reference 1 discloses nanocomposite particlescontaining polystyrene beads or silica colloid beads as nanoparticlesand a phospholipid and lactose as coating substances. The geometricparticle diameter of such nanocomposite particles increases along withan increase in concentration of nanoparticles, but it is disclosed thatthe aerodynamic particle diameter is irrelevant to the concentration ofnanoparticles. Also, it is disclosed that the nanoparticles can beeluted out when the nanocomposite particles are redissolved in ethanol.

Patent Reference 2 discloses a pronanosphere (nanocomposite particles)obtained by coating a nanosphere liposome containing a drug and aphospholipid by using a sugar material as a nucleus and employing afluid bed Granulation method. It is disclosed that by adding water tothe nanocomposite particles it is possible to provide a liposomedispersion liquid in which the liposome has an average particle diameterthat is substantially the same as that of the liposome beforepreparation of the nanocomposite particles.

Further, Patent Reference 3 discloses drug-containing compositeparticles containing biocompatible nanoparticles formed of a drug and abiocompatible polymer, and a sugar alcohol. The drug-containingcomposite particles are produced by a spray drying fluid bed granulationmethod, and are secondary particles formed of primary particles suitablyused for pulmonarily administration.

Patent Reference 1: Japanese National Phase Publication No. 2005-511629

Patent Reference 2: Japanese Patent Application Laid-Open (JP-A) No.05-194196

Patent Reference 3: Japanese Patent Application Laid-Open (JP-A) No.2004-262810

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The nanocomposite particles disclosed in Patent Reference 1 haveinsufficient solubility in water due to the large amount of phospholipidincluded as the coating substance and cannot be said to have sufficientredispersibility in water. Also, since the nanocomposite particlesdisclosed in Patent Reference 2 are prepared by the fluid bedgranulation method, the particle diameter of the nanocomposite particlesthat can be produced is limited and, in particularly, it is difficult toobtain nanocomposite particles having a flying property. Further, sincea nanoparticle dispersion liquid obtained by redispersion in water is aliposome dispersion liquid, stability of the thus-obtained nanoparticledispersion liquid cannot be said to be sufficient. Since thedrug-containing composite particles disclosed in Patent Reference 3 havehigh moisture absorption due to the inclusion of sugar alcohol, handlingproperties as a pulmonary inhalation preparation are insufficient. Also,due to production by the spray drying fluid bed granulation method, thecontained drug is exposed to a high temperature for a long time, as aresult of which the drugs that can be contained are limited.

An object of the invention is to provide nanocomposite particles havinggood solubility in water and exhibiting good redispersibility whenbrought into contact with water.

Means for Solving the Problems

According to a first aspect of the invention, there is providednanocomposite particles comprising a sugar material and nanoparticlesincluding a drug to be delivered and a biodegradable polymer, whereinthe sugar material is disaccharide; and a mass ratio of thenanoparticles to the disaccharide is within a range of from 40:60 to60:40.

In the invention, the mass ratio of the nanoparticles to thedisaccharide is more preferably within a range of from 45:55 to 55:45.

In the invention, the biodegradable polymer is preferably abiodegradable polymer comprising at least one selected from the groupconsisting of polylactic acid, polyglycolic acid, poly(lacticacid-glycolic acid), and polycyanoacrylate.

In the invention, the disaccharide is preferably at least one selectedfrom the group consisting of sucrose, maltose, lactose, trehalose, andcellobiose.

In the invention, it is preferable that the biodegradable polymer is abiodegradable polymer comprising at least one selected from the groupconsisting of polylactic acid, polyglycolic acid, poly(lacticacid-glycolic acid), and polycyanoacrylate and the disaccharide is atleast one selected from the group consisting of sucrose, maltose,lactose, trehalose, and cellobiose, and it is more preferable that thebiodegradable polymer is a biodegradable polymer comprising poly(lacticacid-glycolic acid) and the disaccharide is lactose and/or trehalose.

The nanocomposite particles of the invention are preferably obtained byspray drying a solution comprising the nanoparticles and thedisaccharide. Further, an inlet temperature of a spray drying machine inthe spray drying is preferably within a range of from 60° C. to 100° C.,and the inlet temperature of the spray drying machine is particularlypreferably within a range of from 60° C. to 90° C.

According to a second aspect of the invention, there is provided aproduction method for the nanocomposite particles, comprising spraydrying a solution containing the nanoparticles and the disaccharide.

In the production method of the invention, an inlet temperature of aspray dying machine in the spray drying is preferably within a range offrom 60° C. to 100° C., and the inlet temperature of the spray dryingmachine is particularly preferably within a range of from 60° C. to 90°C.

EFFECT OF THE INVENTION

According to the invention, it is possible to provide nanocompositeparticles having good solubility in water and exhibiting goodredispersibility when brought into contact with water.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A graph showing an aerodynamic particle diameter distribution ofSample (III-2).

BEST MODE FOR CARRYING OUT THE INVENTION

The invention provides nanocomposite particles including a sugarmaterial and nanoparticles containing a drug to be delivered and abiodegradable polymer, wherein the sugar material is disaccharide, and amass ratio of the nanoparticles to the disaccharide is within the rangeof from 40:60 to 60:40.

As used herein, the term “nanoparticles” means fine particles having anaverage particle diameter of less than 1 μm. It is possible to measurethe average particle diameter of nanoparticles by a method known in theart (e.g. by using a commercially available wet particle diametermeasurement device). From the view points of absorption to living bodyand retention control in living body of the nanoparticles, the averageparticle diameter is preferably within the range of from 50 to 900 nm,more preferably from 250 to 900 nm. The particle diameter of thenanoparticles may be chanced depending on the purpose of usage. Also,since the nanoparticles generally have an average particle diameter ofless than 1 μm, it is possible to avoid phagocytosis by alveolarmacrophage.

Examples of the drug to be delivered contained in the nanoparticles inthe invention include a physiologically active substance and adiagnostic agent. Examples of biological activity of the physiologicallyactive substance include therapeutic, diagnostic, and prophylacticactivities. Such drugs to be delivered may be used alone or incombination of two or more.

Examples of the physiologically active substance include an inorganiccompound, an organic compound, a polypeptide, a nucleic acid, apolysaccharide, and the like having therapeutic, diagnostic, and/orprophylactic activities. Also, examples of a biological activity of thephysiologically active substance include a vascular action, aneurotropic action, a hormone action, an anticoagulant action, an immuneregulating action, an anti-inflammatory/analgesic action, anantibacterial action, an antitumor action, an antivirus action, anantigen action, an antibody action, an antisense action, and the likewithout limitation thereto.

As used herein, the term “polypeptide” means those containing two ormore amino acids and having an arbitrary size irrespective ofpresence/absence of modification after translation, such asglycosylation, phosphorylation, or the like. Examples of the polypeptideinclude a complete protein such as insulin, calcitonin, immune globulin,an antibody, a cytokine (e.g. lymphokine, monokine, chemokine), aninterleukin, an interferon, an erythropoietin, a nuclease, a tumornecrosis factor, a colony stimulation factor, an enzyme (e.g. superoxidedismutase, tissue plasminogen activator agent), a tumor suppressor, ablood protein, a hormone, and a hormone analogue (e.g. growth hormone,adrenocorticotropic hormone, luteinizing hormone-releasing hormone), avaccine (e.g. tumor antigen, bacterial antigen, virus antigen), anantigen, a blood coagulation factor, a growth factor, and a granulocytecolony simulation factor, a mutein, and active fragments thereof.Examples of physiologically active actions of the polypeptide include aprotein inhibitor, a protein antagonist, and a protein agonist withoutlimitation thereto. As used herein, the term “nucleic acid” means apolynucleotide having a DNA sequence or an RNA sequence having anarbitrary length, and examples thereof include a gene (e.g. antisensemolecule capable of linking to a complementary DNA for inhibitingtranscription, etc.) and ribozyme. Also, polysaccharide such as heparinmay be used.

The nanoparticles of the invention may contain a physiologically activesubstance for the purpose of detecting an analysis object for diagnosis.Examples of the physiologically active substance include an antigen, anantibody (monochlonal or polychlonal), a receptor, hapten, an enzyme, aprotein, polypeptide, a nucleic acid (e.g. DNA or RNA), a hormone, and apolymer, and the nanoparticles may contain at least one of thephysiologically active substances. Also, the nanoparticles may belabeled in order to facilitate detection of the nanoparticles. Examplesof the label include various enzymes, a fluorescent substance, aluminescent substance, a bioluminescent substance, and a radioactivesubstance without limitation thereto. Appropriate examples of theenzymes include horse radish peroxidase, alkaline phosphatase,β-galactosidase, and acetylcholine esterase. Appropriate examples of thefluorescent substance include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinyl amine fluorescein, dansylchloride, and phycoerythrin. Examples of the luminescent substanceinclude luminol. Examples of the bioluminescent substance includeluciferase, luciferin, and aequorin. Appropriate examples of theradioactive substance include ¹²⁵I, ¹³¹I, ³⁵S, and ³H.

Particularly useful examples of the physiologically active substanceinclude, from the view points of systemic and local therapies, varioushormones (e.g. insulin, estradiol, etc.), therapeutic drugs for asthma(e.g. albuterol, etc.), therapeutic drugs for tuberculosis (e.g.rifampicin, ethambutol, streptomycin, isoniazid, pyrazine amide, etc.),therapeutic drugs for cancer (e.g. cisplatin, carboplatin, adriamycin,5-FU, paclitaxel, etc.), and therapeutic drugs for high blood pressure(e.g. clonidine, prazosin, propranolol, labetalol, bunitrolol,reserpine, nifedipine, furosemide, etc.) without limitation thereto.

The nanoparticles may contain an arbitrary diagnostic agent. It ispossible to locally or systemically deliver the diagnostic agent byadministering such nanocomposite particles to a patient. Specificexamples of the diagnostic agent include a contrast agent withoutlimitation thereto. Examples of the contrast agent include commerciallyavailable drugs used in positron emission tomography (PET), computedtomography (CT), single photon emission computed tomography, X-ray,X-ray fluoroscopy, and magnetic resonance imaging (MRI). The diagnosticagent may be detected by employing the standard technology available inthe art and a commercially available apparatus.

From the view points of stability of the nanoparticles and stability ofthe drug to be delivered, the nanoparticles may contain a drug in anamount of 1 to 50 mass %, preferably 5 to 20 mass %, of a mass of thenanoparticles. It is possible to change the content of the drugdepending on a desired effect and a release rate or a release period ofthe drug to be delivered.

The nanoparticles in the invention contain a biodegradable polymer. Ingeneral, the biodegradable polymer is degraded to a substance harmlessto living body by enzymatic degradation or exposure to water in vivo.Examples of the biodegradable polymer include a polyester compound, apolyamide compound, a polycarbonate compound, a polyvinyl compound, andpolysaccharide without limitation thereto. These biodegradable polymersmay be used alone or in combination of two or more.

Specific examples of the polyester compound include polylactic acid,polyglycolic acid, polycaprolactone, and copolymers thereof, as well aspolybutylene succinate, polyethylene succinate, poly(butylenesuccinate/adipate), poly(butylene succinate/carbonate), poly(butylenesuccinate/telephthalate), poly(butylene adipate/telephthalate),poly(tetramethylene adipate/telephthalate), and poly(butylenesuccinate/adipate/telephthalate) without limitation thereto.

Specific examples of the polyamide compound include polyleucine,specific examples of the polyvinyl compound include polycyanoacrylate,and specific examples of the polysaccharide include cellulose withoutlimitation thereto.

Among these biodegradable polymers, it is preferable to use at least oneselected from polylactic acid, polyglycolic acid, poly(lacticacid-glycolic acid) (PLGA), and polycyanoacrylate, and it is morepreferable to use PLGA.

By appropriately selecting a type and a molecular weight of thebiodegradable polymer, it is possible to control a release rate of thedrug from the nanoparticles and a biodegradation rate. For example, inthe case where the biodegradable polymer is PLGA, the molecular weightis preferably 1500 to 150000, more preferably 1500 to 75000. It ispossible to provide the nanoparticles capable of easily releasing abiodegradable substance. Also, in the case where the biodegradablepolymer is a copolymer, it is possible to control the release rate ofthe drug from nanoparticles and the biodegradation rate by appropriatelyselecting a composition ratio of each of monomers.

Further, the nanoparticles may be modified so as to control the releaserate of the drug from nanoparticles and the biodegradation rate.

The nanoparticles may contain various additives as required. Specificexamples of the additives include a surfactant, a water soluble polymer,and a lipid without limitation thereto. It is possible to furtherenhance the redispersibility of the nanoparticles by adding suchadditives. Specific examples of the water soluble polymer includepolyvinyl alcohol, polyethylene glycol, polyethylene oxide, and thelike, and specific examples of the lipid include phospholipid,cholesterol, and the like. These additives may be used alone or incombination of two or more.

It is possible to prepare the nanoparticles in the invention by a methodknown in the art, such as dry milling, wet milling, emulsionpolymerization, interfacial polymerization, spray drying, thermofusionmicroencapsulation, emulsion solvent diffusion, and the like withoutlimitation thereto. Particularly, from the view point of easy particlediameter control, the emulsion solvent diffusion method employingsupersonic emulsification may preferably be employed.

The nanocomposite particles of the invention contain the nanoparticlesand the disaccharide, and a large part thereof has a structure whereinthe nanoparticles and the disaccharide form a network. Since thenanocomposite particles contain the disaccharide, it is possible toobtain the nanocomposite particles that are excellent inredispersibility of nanoparticles and handling property.

The disaccharide is not particularly limited insofar as the disaccharideis obtained by bonding of two molecules of monosaccharide (e.g. glucose,fructose, galactose, etc.). A combination of the monosaccharide is notparticularly limited, but, from the view points of redispersibility ofthe nanoparticles and handling property, any one of two molecules ofglucose, glucose and fructose, galactose and glucose is preferred. Also,a mode of glycoside bonding is not limited, and the bonding may be anyone of an α1,4 bonding, a β1,4 bonding, and a 1,1 bonding. Specificexamples of the disaccharide include sucrose, maltose, lactose,trehalose, cellobiose, and the like.

In the invention, it is preferable to use at least one selected fromsucrose, maltose, lactose, trehalose, and cellobiose among theabove-listed disaccharide from the view points of water solubility ofdisaccharide, redispersibility of nanoparticles, and handling propertyof nanocomposite particles, and it is more preferable to use at leastone selected from trehalose and lactose. These disaccharides may be usedalone or in combination of two or more.

A mass ratio of the nanoparticles to the disaccharide in thenanocomposite particles of the invention is within the range of from40:60 to 60:40 from the view point of redispersibility of thenanoparticles. There is a tendency of incomplete redispersion ofnanocomposite particles when the mass ratio is outside the range. Thatis, although the nanocomposite particles partly release thenanoparticles contained therein, the rest causes coagulation orinsolubilization so that a particle diameter distribution of theredispersion liquid has a polydisperse system. Further, it is possibleto achieve a better particle diameter distribution by maintaining themass ratio within the more preferable range of from 45:55 to 55:45.

The nanocomposite particles of the invention may contain variousadditives as required. Examples of the additives include a buffer salt,a fatty acid, a fatty acid ester, a phospholipid, an inorganic compound,a phosphate, and the like.

It is possible to prepare the nanocomposite particles of the inventionby a method known in the art. For example, it is possible to employ aspray drying method, a membrane emulsification method, freeze drying, atumbling granulation method, a fluid bed granulation method, and thelike without limitation thereto. Particularly, it is preferable toperform the preparation by employing the spray drying method from theview points of capability of easy particle diameter control and theshort particle drying time.

One of ordinarily employed spray drying techniques is disclosed in SprayDrying Handbook, K. Masters, John Wiley & Sons, New York, 1984. Ingeneral, in the spray drying, a heat derived from a heated gas such as aheated air or heated nitrogen is used for evaporating a solvent fromdroplets formed by an spraying device under a temperature gradientbetween an inlet temperature immediately after spraying and an outlettemperature at termination of drying, thereby obtaining spray driedparticles.

For the spraying device, an spraying technology known in the art may beemployed. For example, a liquid pressure press nozzle spraying device, atwo-stream spraying device, a supersonic spraying device, a centrifugalspraying device including a rotating plate or a wheel are usable withoutlimitation thereto.

It is possible to prepare the nanocomposite particles of the inventionby using a commercially available spray drying machine, for example. Aninlet temperature in a drying zone immediately after spraying mayappropriately be selected depending on the spray drying machine to beused, the composition of the nanoparticle dispersion liquid to be spraydried, and the like and may preferably be within the range of from 60°C. to 100° C., more preferably within the range of from 60° C. to 90° C.In the case where the inlet temperature is low, a reduction inproductivity and an increase in average particle diameter tends to occurdue to insufficient drying rate. Also, in the case where the inlettemperature is too high, good redispersibility is not achieved in somecases. It is possible to assume that such case is attributable toalteration of disaccharide by the high temperature.

Particularly, in the case of using the nanocomposite particles as apulmonary administration preparation, the inlet temperature maypreferably be 70° C. to 120° C., more preferably 80° C. to 120° C., inorder to obtain nanocomposite particles having an aerodynamic particlediameter.

It is possible to measure or calculate the aerodynamic particle diameterby a method known in the art. For example, it is possible to perform themeasurement by using a cascade impactor employing aerodynamicclassification mechanism. Also, the aerodynamic particle diameter(d_(aer)) is calculated from the following expression (1) using ageometric particle diameter (d_(s)) and a density (ρ).

d _(aer) =d _(s)×square root of ρ  (1).

The cascade impactor is used for evaluating the aerodynamic particlediameter distribution of pulmonary absorption preparations, and it ispossible to perform the evaluation in accordance with US pharmacopeia.For instance, the method using an Andersen type cascade impactor is amethod for evaluating the aerodynamic particle diameter distribution bymeasuring to which stage among stages 0 to 7 a fine powder charged froman upper part of the device reaches while sucking with a pump. The upperthe stage, the larger the sieve opening, and the lower the stage, thesmaller the sieve opening. Therefore, the particles deposited on theupper stage have a larger aerodynamic particle diameter. Morespecifically, particles having an aerodynamic particle diameter largerthan 4.7 μm are deposited on the stages 0 to 2, and particles having anaerodynamic particle diameter of from 0.13 to 4.7 μm are deposited onthe stages 3 to 7. It is possible to evaluate the aerodynamic particlediameter by measuring a mass of particles deposited in each of thestages.

Water or a buffer solution is used as a solvent for preparing a sugarsolution in which the nanoparticles to be used for the spray drying aredispersed. An organic solvent may also be contained. Appropriateexamples of the organic solvent include an alcohol (e.g. methanol,ethanol, propanol, isopropyl alcohol, butanol, etc.), perfluorocarbon,dichloromethane, chloroform, ether, ethyl acetate,methyl-tert-butylether, acetone, and the like without limitationthereto.

The nanocomposite particles of the invention are useful as a pulmonaryabsorption preparation in the case where the nanocomposite particles areprepared so as to have an aerodynamic particle diameter appropriate fordelivery to the alveoli. Also, since the nanocomposite particles of theinvention have high water solubility, they are useful for an injectionpreparation, an oral absorption preparation, a transmucosal absorptionpreparation, a transdermal absorption preparation, and an ophthalmicpreparation due.

Hereinafter, specific examples of the invention will be described todescribe the invention in more details. However, the invention is notlimited to the examples.

Example 1 (1) Preparation of Nanoparticles

In 10 mL of dichloromethane, 0.05 g of rifampicin and 0.45 g of PLGA(lactic acid:glycolic acid=75:25, molecular weight: 10000) weredissolved, and the mixture was added to 100 mL of a polyvinyl alcohol(manufactured by Wako Pure Chemical Industries, polymerization degree:about 500) aqueous solution. By using a supersonic wave generator(S-250D manufactured by BRANSON), irradiation with a supersonic wave atan output of 110 W was performed for 20 seconds. The thus-obtained O/Wemulsion was stirred for 3 hours at a room temperature to evaporatedichloromethane. The thus-obtained S/W dispersion liquid was subjectedto centrifugation at 10000 rpm for 10 minutes, followed by collection ofprecipitated rifampicin-containing PLGA nanoparticles. Distilled waterwas added to the nanoparticles to perform redispersion, andcentrifugation at 10000 rpm was performed for 10 minutes again, followedby collection of precipitated nanoparticles. This operation was repeatedfor three times.

The thus-obtained nanoparticles were dispersed in distilled water, and aparticle diameter distribution was measured by using a wet particlediameter measurement device (ZETA SIZER HSA3000 manufactured byMALVERN). The thus-obtained nanoparticles exhibited a particle diameterdistribution of a single dispersion. An average particle diameterthereof was about 500 nm.

(2) Preparation of Nanocomposite Particles

The PLGA nanoparticles obtained by the above-described nanoparticlepreparation method were redispersed in 100 mL of a distilled water byvarying a mass thereof as shown in Table 1 to Table 6, and trehalose wasadded to and dissolved in each of the dispersion liquids by varying amass thereof as shown in Table 1 to Table 6. Each of the trehalosesolutions in which the nanoparticles were dispersed was supplied to aspray drying machine (Minispray Dryer B290 Type manufactured by BUCHI)to prepare nanocomposite particles. Conditions for the spray drying werea spray gun diameter of 0.75 mm, an inlet temperature of 90° C., adrying air amount of 22 m³/hr, a spraying air amount of 536 L/hr, and asample supply rate of 1.2 mL/min.

(3) Measurement of Dry Average Particle Diameter Distribution ofNanocomposite Particles

A particle diameter distribution in the air of the nanocompositeparticles obtained as described above was measured by using a dryparticle diameter measurement device (LDSA-3500A manufactured by TonichiComputer Applications Co., Ltd.) to calculate a dry average particlediameter (d_(s))(μm).

(4) Measurement of Specific Gravity of Nanocomposite Particles andCalculation of Aerodynamic Particle Diameter

A specific gravity of the nanocomposite particles obtained as describeabove was measured by using a particle specific gravity meter(ULTRAPYCOMETER1000 manufactured by Quantachrome Inc.). An aerodynamicparticle diameter (d_(aer))(μm) of the particles was calculated by thefollowing expression (1) by using the dry particle diameter (d_(s))(μm)and a particle density (ρ).

d _(aer) =d _(s)×square root of ρ  (1).

(5) Measurement of Wet Particle Diameter Distribution of NanocompositeParticles

Next, 0.005 g of the nanocomposite particles were redispersed in 10 mLof distilled water, and a wet particle diameter distribution thereof wasmeasured by using a wet particle diameter measurement device (ZETA SIZERHSA3000 manufactured by MALVERN). The measurement was performedimmediately after the redispersion and also at 10 minutes after theredispersion as required.

The masses of the nanoparticles and trehalose, the measurement resultsof the dry average particle diameters, and the measurement results ofthe wet particle diameter distributions of the obtained nanocompositeparticles are shown in Table 1 to Table 6.

TABLE 1 Sample No. I-1 Sample No. I-2 Nanoparticles (g) 0.2Nanoparticles (g) 0.4 Trehalose (g) 1.8 Trehalose (g) 1.6 Dry AverageParticle 2.12 Dry Average Particle 2.47 Diameter (μm) Diameter (μm)Specific Gravity 1.49 Specific Gravity 1.44 Aerodynamic Particle 2.59Aerodynamic Particle 2.97 Diameter (μm) Diameter (μm) Wet Particle WetParticle Wet Particle Wet Particle Diameter Distribution DiameterDistribution Diameter Distribution Diameter Distribution (immediatelyafter) (10 minutes after) (immediately after) 10 minutes after) ParticleVolume Particle Volume Particle Volume Particle Volume Diameter (nm) (%)Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)  33 0.0 36 0.0 150.0 24 0.0  44 0.0 47 0.0 21 0.0 31 0.0  59 0.0 62 0.0 29 0.0 42 0.0  780.0 82 0.0 41 0.0 55 0.0  104 0.0 108 0.0 57 0.0 73 0.0  139 0.0 142 0.080 0.0 97 0.0  185 0.0 187 0.0 111 0.0 129 0.0  247 0.0 247 0.1 156 0.0171 0.0  329 0.8 325 4.6 217 0.0 227 0.1  439 1.6 429 9.4 304 6.0 3017.1  585 1.3 565 13.1 425 12.4 400 16.2  779 1.9 745 19.0 594 6.9 53117.0 1038 2.9 981 18.4 831 0.5 704 13.2 1384 2.0 1293 13.9 1161 0.0 9355.4 1844 1.0 1704 11.1 1623 0.0 1241 0.0 2458 0.6 2245 7.6 2269 0.0 16470.0 3277 0.2 2959 2.8 3172 0.0 2186 6.6 4367 0.2 3899 0.0 4434 3.4 290116.8 5820 0.7 5139 0.0 6199 22.0 3850 13.9 7758 2.5 6771 0.0 8666 33.85110 3.7 10339  23.4 8923 0.0 12115 15.2 6781 0.0 13781  41.1 11759 0.016937 0.0 9000 0.0 18367  19.7 15496 0.0 23677 0.5 11945 0.0 24480  0.020420 0.0 33100 0.0 15854 0.0 Average 12074.6 Average 1073.9 Average6519.6 Average 1675.8 Particle Particle Particle Particle DiameterDiameter Diameter Diameter (nm) (nm) (nm) (nm) Remarks ComparativeExample Remarks Comparative Example

TABLE 2 Sample No. I-3 Sample No. I-4 Nanoparticles (g) 0.6Nanoparticles (g) 0.8 Trehalose (g) 1.4 Trehalose (g) 1.2 Dry AverageParticle 2.07 Dry Average Particle 1.77 Diameter (μm) Diameter (μm)Specific Gravity 1.43 Specific Gravity 1.44 Aerodynamic Particle 2.48Aerodynamic Particle 2.12 Diameter (μm) Diameter (μm) Wet Particle WetParticle Wet Particle Wet Particle Diameter Distribution DiameterDistribution Diameter Distribution Diameter Distribution (immediatelyafter) (10 minutes after) (immediately after) (10 minutes after)Particle Volume Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)   7 0.021 0.0 70 0.0 14 0.0  11 0.0 28 0.0 82 0.0 19 0.0  16 0.0 37 0.0 97 0.026 0.0  23 0.0 49 0.0 114 0.0 35 0.0  34 0.0 65 0.0 134 0.0 48 0.0  500.0 86 0.0 157 0.0 66 0.0  73 0.0 115 0.0 185 0.0 91 0.0  107 0.0 1530.0 217 0.0 125 0.2  157 0.1 203 0.3 255 0.0 172 0.7  230 1.1 270 3.9300 1.4 237 1.7  337 4.7 358 15.9 353 22.7 326 19.6  495 9.4 477 22.2415 44.9 448 38.1  726 8.7 633 10.9 488 27.3 616 24.5 1066 2.9 842 1.0574 3.7 847 8.5 1563 0.0 1120 3.0 675 0.0 1165 5.2 2294 0.0 1488 14.5794 0.0 1602 1.4 3365 0.0 1979 19.8 934 0.0 2202 0.0 4938 0.0 2631 8.41098 0.0 3028 0.0 7245 18.3 3497 0.0 1291 0.0 4164 0.0 10629  36.6 46490.0 1518 0.0 5725 0.0 15596  18.3 6181 0.0 1785 0.0 7871 0.0 22882  0.08218 0.0 2099 0.0 10823 0.0 33574  0.0 10925 0.0 2468 0.0 14881 0.049260  0.0 14524 0.0 2902 0.0 20460 0.0 Average 8229.3 Average 1113.5Average 425.4 Average 546.2 Particle Particle Particle Particle DiameterDiameter Diameter Diameter (nm) (nm) (nm) (nm) Remarks ComparativeExample Remarks Example

TABLE 3 Sample No. I-5 Sample No. I-6 Nanoparticles (g) 0.9Nanoparticles (g) 1.0 Trehalose (g) 1.1 Trehalose (g) 1.0 Dry AverageParticle 1.77 Dry Average Particle 1.86 Diameter (μm) Diameter (μm)Specific Gravity 1.33 Specific Gravity 1.31 Aerodynamic Particle 2.04Aerodynamic Particle 2.13 Diameter (μm) Diameter (μm) Wet Particle WetParticle Wet Particle Wet Particle Diameter Distribution DiameterDistribution Diameter Distribution Diameter Distribution (immediatelyafter) (10 minutes after) (immediately after) (10 minutes after)Particle Volume Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)  66 0.036 0.0 111 0.0 107 0.0  79 0.0 45 0.0 125 0.0 121 0.0  94 0.0 57 0.0 1400.0 137 0.0 113 0.0 72 0.0 158 0.0 155 0.0 135 0.0 90 0.0 178 0.0 1750.0 161 0.0 113 0.0 200 0.0 198 0.0 193 0.0 143 0.0 225 0.0 224 0.0 2310.0 180 0.0 253 0.3 254 0.0 276 0.0 226 0.2 285 1.4 287 0.2 331 8.4 2851.9 320 4.4 325 2.4 396 31.1 358 19.2 361 16.1 368 21.1 474 39.3 45135.0 406 33.3 417 41.3 567 18.9 568 24.8 457 31.2 472 28.1 678 2.3 71513.0 514 11.9 535 6.3 811 0.0 900 5.7 578 1.2 605 0.5 971 0.0 1133 0.0650 0.1 685 0.0 1161  0.0 1427 0.0 732 0.0 776 0.0 1390  0.0 1796 0.0824 0.0 878 0.0 1663  0.0 2261 0.0 927 0.0 994 0.0 1989  0.0 2846 0.01043 0.0 1126 0.0 2381  0.0 3583 0.0 1173 0.0 1275 0.0 2848  0.0 45110.0 1320 0.0 1443 0.0 3408  0.0 5678 0.0 1486 0.0 1634 0.0 4078  0.07148 0.0 1672 0.0 1649 0.0 Average 459.6 Average 517.8 Average 423.1Average 427.8 Particle Particle Particle Particle Diameter DiameterDiameter Diameter (nm) (nm) (nm) (nm) Remarks Example Remarks Example

TABLE 4 Sample No. I-7 Sample No. I-8 Nanoparticles (g) 1.1Nanoparticles (g) 1.2 Trehalose (g) 0.9 Trehalose (g) 0.8 Dry AverageParticle 1.58 Dry Average Particle 1.99 Diameter (μm) Diameter (μm)Specific Gravity 1.45 Specific Gravity 1.39 Aerodynamic Particle 1.90Aerodynamic Particle 2.35 Diameter (μm) Diameter (μm) Wet Particle WetParticle Wet Particle Wet Particle Diameter Distribution DiameterDistribution Diameter Distribution Diameter Distribution (immediatelyafter) (10 minutes after) (immediately after) (10 minutes after)Particle Volume Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)  82 0.042 0.0 303 0.0 21 0.0  96 0.0 52 0.0 321 0.0 28 0.0  113 0.0 65 0.0 3410.0 38 0.0  133 0.0 80 0.0 361 0.0 50 0.0  156 0.0 99 0.0 383 0.0 66 0.0 184 0.0 123 0.1 406 0.0 88 0.0  216 0.0 152 0.1 430 4.8 117 0.0  2540.1 189 0.1 456 15.2 155 0.2  298 1.2 234 0.3 483 20.7 205 0.9  351 13.8290 1.7 512 19.4 272 4.4  412 29.9 359 19.0 543 16.2 361 17.1  485 24.1445 35.7 576 12.4 478 28.8  570 12.3 552 24.2 610 7.7 634 24.2  670 10.2684 11.6 647 3.0 841 14.8  788 6.7 848 6.3 686 0.5 1116 7.8  927 1.71051 0.9 727 0.0 1480 2.1 1090 0.0 1303 0.0 770 0.0 1962 0.0 1281 0.01615 0.0 817 0.0 2602 0.0 1507 0.0 2002 0.0 866 0.0 3451 0.0 1772 0.02482 0.0 918 0.0 4577 0.0 2083 0.0 3076 0.0 973 0.0 6070 0.0 2449 0.03813 0.0 1031 0.0 8049 0.0 2880 0.0 4726 0.0 1093 0.0 10674 0.0 3386 0.05858 0.0 1158 0.0 14156 0.0 Average 499.5 Average 509.2 Average 518.5Average 608.1 Particle Particle Particle Particle Diameter DiameterDiameter Diameter (nm) (nm) (nm) (nm) Remarks Example Remarks Example

TABLE 5 Sample No. I-9 Sample No. I-10 Nanoparticles (g) 1.4Nanoparticles (g) 1.6 Trehalose (g) 0.6 Trehalose (g) 0.4 Dry AverageParticle 2.52 Dry Average Particle 1.91 Diameter (μm) Diameter (μm)Specific Gravity 1.38 Specific Gravity 1.35 Aerodynamic Particle 2.96Aerodynamic Particle 2.22 Diameter (μm) Diameter (μm) Wet Particle WetParticle Wet Particle Wet Particle Diameter Distribution DiameterDistribution Diameter Distribution Diameter Distribution (immediatelyafter) (10 minutes after) (immediately after) (10 minutes after)Particle Volume Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)  23 0.024 0.0 1 0.0 17 0.0  31 0.0 32 0.0 2 0.0 23 0.0  42 0.0 43 0.0 4 0.0 320.0  57 0.0 58 0.0 7 0.0 44 0.0  76 0.0 77 0.0 11 0.0 61 0.0 102 0.0 1040.0 20 0.0 84 0.0 138 0.0 139 0.0 34 0.0 115 0.0 185 0.0 186 0.0 59 0.0158 0.2 248 0.4 249 0.4 102 0.0 217 0.5 334 12.8 333 12.9 177 0.5 2996.9 448 25.7 446 26.1 307 10.7 411 13.9 602 15.7 597 16.7 532 34.7 56514.3 809 4.4 799 6.0 923 39.3 776 19.6 1087  4.1 1070 4.4 1599 14.8 106821.6 1460  11.5 1432 8.5 2772 0.0 1468 12.4 1961  17.3 1918 14.6 48040.0 2018 6.1 2635  8.0 2568 9.0 8327 0.0 2774 3.5 3540  0.0 3438 1.314432 0.0 3814 0.9 4756  0.0 4604 0.0 25013 0.0 5244 0.0 6390  0.0 61640.0 43352 0.0 7210 0.0 8585  0.0 8254 0.0 75137 0.0 9912 0.0 11534  0.011052 0.0 130228 0.0 13628 0.0 15497  0.0 14798 0.0 225710 0.0 18736 0.020820  0.0 19814 0.0 391198 0.0 25760 0.0 Average 1051.4 Average 1032.5Average 817.8 Average 979.1 Particle Particle Particle Particle DiameterDiameter Diameter Diameter (nm) (nm) (nm) (nm) Remarks ComparativeExample Remarks Comparative Example

TABLE 6 Sample No. I-11 Sample No. I-12 Nanoparticles (g) 1.8Nanoparticles (g) 2.0 Trehalose (g) 0.2 Trehalose (g) 0.0 Dry AverageParticle 1.98 Dry Average Particle 1.80 Diameter (μm) Diameter (μm)Specific Gravity 1.31 Specific Gravity 1.34 Aerodynamic Particle 2.27Aerodynamic Particle 2.08 Diameter (μm) Diameter (μm) Wet Particle WetParticle Wet Particle Wet Particle Diameter Distribution DiameterDistribution Diameter Distribution Diameter Distribution (immediatelyafter) (10 minutes after) (immediately after) (10 minutes after)Particle Volume Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)  17 0.016 0.0 6 0.0 6 0.0  23 0.0 22 0.0 9 0.0 9 0.0  32 0.0 30 0.0 14 0.0 140.0  44 0.0 42 0.0 21 0.0 22 0.0  60 0.0 57 0.0 31 0.0 34 0.0  82 0.0 790.0 47 0.0 52 0.0 113 0.0 108 0.0 70 0.0 79 0.0 156 0.0 149 0.1 105 0.0122 0.1 215 0.3 205 0.4 158 0.0 187 0.3 295 6.3 281 2.2 237 0.9 287 5.7406 13.1 386 4.7 355 8.6 441 12.2 559 14.5 531 14.9 532 31.8 677 16.8769 17.5 730 29.2 797 41.4 1039 26.5 1058  14.2 1003 26.0 1194 17.3 159625.8 1455  4.7 1379 13.7 1789 0.0 2449 11.0 2002  4.2 1895 6.7 2680 0.03760 1.6 2754  10.4 2605 1.9 4016 0.0 5772 0.0 3790  10.4 3581 0.0 60180.0 8861 0.0 5214  3.9 4921 0.0 9019 0.0 13602 0.0 7173  0.3 6764 0.013514 0.0 20881 0.0 9869  0.0 9297 0.0 20251 0.0 32054 0.0 13577  0.012778 0.0 30346 0.0 49207 0.0 18680  0.0 17563 0.0 45472 0.0 75539 0.025700  0.0 24140 0.0 68140 0.0 115961 0.0 Average 1496.1 Average 943.8Average 738.0 Average 1201.2 Particle Particle Particle ParticleDiameter Diameter Diameter Diameter (nm) (nm) (nm) (nm) RemarksComparative Example Remarks Comparative Example

Each of the dry particle diameter distributions of nanocompositeparticles of Sample Nos. I-1 to I-12 gave a single peak. It is revealedthat the average particle diameter is about 2 μm without depending onthe mass ratio of the nanoparticles to trehalose.

It is possible to evaluate redispersibility of nanoparticles by themeasurement of wet particle diameter distribution of the nanocompositeparticles obtained by the invention. It is possible to evaluatedispersion stability of the nanoparticles dispersion liquid by comparingresults obtained by performing the measurement of the wet particlediameter distribution twice, namely, immediately after the addition ofwater and at 10 minutes after the addition of water.

It is apparent from Table 1 to Table 6 that each of the wet particlediameter distributions of the nanocomposite particles of Sample Nos. I-4to I-8 gave a single peak, and the obtained nanoparticle dispersionliquid is of a monodisperse system. It is apparent that each of the wetparticle diameter distributions of the nanocomposite particles of SampleNos. 1-5 to 1-7 exhibits good redispersibility with a narrowerdistribution width. An average particle diameter is about 500 nm, whichis substantially the same as that of the nanoparticles before thenanocomposite particle preparation. Also, since no major chance isobserved with the particle diameter distribution in the measurement of10 minutes after the water addition, it is proved that the nanoparticledispersion liquid is stable.

In contrast, each of the wet particle diameter distributions of thenanocomposite particles of Sample Nos. I-1 to I-3 and 1-9 to 1-12 gavetwo peaks, from which it is apparent that the nanoparticles are notcompletely redispersed. Also, since no major change is observed with thewet particle diameter distribution in the measurement of 10 minutesafter the water addition, it is proved that the nanoparticles are notcompletely redispersed.

As a summary of the foregoing results, it is proved that thenanocomposite particles of Sample Nos. I-4 to I-8 having the mass ratioof the nanoparticles to trehalose within the range of from 40:60 to60:40 exhibit good redispersibility. Also, it is proved that thenanocomposite particles of Sample Nos. I-5 to I-7 having the mass ratioof the nanoparticles to trehalose within the range of from 45:55 to55:45 exhibit better redispersibility.

Example 2 (1) Preparation of Nanoparticles

Rifampicin-containing PLGA nanoparticles were prepared iii the samemanner as in Example 1 except for changing the supersonic waveirradiation conditions from “output: 10 W for 20 seconds” to ; “output:20 W for 60 seconds”.

The obtained PLGA nanoparticles were dispersed in distilled water, and,by a measurement of a particle diameter distribution using the wetparticle diameter measurement device (ZETA SIZER HSA3000 manufactured byMALVERN), a particle diameter distribution having an average particlediameter of about 800 nm and a single peak were shown.

(2) Preparation and Measurements of Wet and Dry Particle DiameterDistributions of Nanocomposite Particles

Nanocomposite particles were prepared in the same manner as in Example 1except for using the nanoparticles (average particle diameter: about 800nm) obtained as described above, and a dry particle diameterdistribution and a wet particle diameter distribution were measured.Results are shown in Table 7.

TABLE 7 Sample No. II-1 II-2 II-3 Nanoparticles (g) 0.9 1.0 1.1Trehalose (g) 1.1 1.0 0.9 Dry Average Particle Diameter (μm) 1.78 1.81.57 Specific Gravity 1.46 1.45 1.44 Aerodynamic Particle Diameter (μm)2.15 2.16 1.88 Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Wet Particle 120 0.0 6 0.05 0.0 Diameter Distribution 142 0.0 9 0.0 8 0.0 (immediately after) 1680.0 14 0.0 12 0.0 198 0.0 21 0.0 18 0.0 233 0.0 33 0.0 29 0.0 275 0.0 510.0 44 0.0 325 0.0 78 0.0 69 0.0 383 0.0 120 0.0 107 0.0 452 0.4 184 0.0167 0.0 533 2.5 283 2.7 260 2.4 629 24.5 436 9.3 404 10.7 742 44.8 67228.9 628 30.8 875 24.5 1034 40.7 978 39.3 1033 2.7 1592 18.4 1521 16.71218 0.5 2451 0.0 2367 0.0 1437 0.0 3773 0.0 3682 0.0 1696 0.0 5809 0.05729 0.0 2001 0.0 8943 0.0 8914 0.0 2361 0.0 13767 0.0 13870 0.0 27850.0 21195 0.0 21580 0.0 3286 0.0 32630 0.0 33575 0.0 3877 0.0 50234 0.052240 0.0 4574 0.0 77336 0.0 81279 0.0 5396 0.0 119060 0.0 126461 0.0Average Particle 749.9 956.2 881.3 Diameter (nm) Remarks Example ExampleExample

From the measurement result of the wet particle diameter distribution,it is revealed that good redispersibility is exhibited when the massratio of the nanoparticles to trehalose is within the range of from45:55 to 55:45 in the case where the nanocomposite particles wereprepared by using the nanoparticles having the average particle diameterof about 800 nm.

Example 3 (1) Preparation of Nanoparticles

Rifampicin-containing PLGA nanoparticles were prepared in the samemanner as in Example 1 except for changing the supersonic waveirradiation time from “20 seconds” to “5 minutes” and changing thecentrifugation conditions from “10000 rpm for 10 minutes” to “35000 rpmfor 15 minutes”.

The obtained PLGA nanoparticles were dispersed in distilled water, and,by a measurement of a particle diameter distribution using the wetparticle diameter measurement device (ZETA SIZER HSA3000 manufactured byMALVERN), a particle diameter distribution having an average particlediameter of about 250 nm and a single peak was shown.

(2) Preparation and Measurements of Dry Particle Diameter and WetParticle Diameter Distribution of Nanocomposite Particles

Nanocomposite particles were prepared in the same manner as in Example 1except for using the nanoparticles (average particle diameter: about 250nm) obtained as described above, and a dry average particle diameter anda wet particle diameter distribution were measured. Results are shown inTable 8.

TABLE 8 Sample No. III-1 III-2 III-3 Nanoparticles (g) 0.9 1.0 1.1Trehalose (g) 1.1 1.0 0.9 Dry Average Particle Diameter (μm) 2.08 2.162.22 Specific Gravity 1.48 1.43 1.39 Aerodynamic Particle Diameter (μm)2.53 2.58 2.61 Particle Volume Particle Volume Particle Volume Diameter(nm) (%) Diameter (nm) (%) Diameter (nm) (%) Wet Particle 9 0.0 9 0.0 140.0 Diameter Distribution 12 0.0 12 0.0 18 0.0 (immediately after) 170.0 16 0.0 23 0.0 23 0.0 22 0.0 30 0.0 31 0.0 30 0.0 39 0.0 42 0.0 410.0 50 0.0 57 0.0 55 0.0 65 0.0 77 0.7 74 0.0 84 0.5 105 3.1 101 0.0 1092.5 143 6.5 136 10.2 142 5.7 194 9.7 184 32.8 183 8.7 264 17.4 249 37.4237 11.2 358 28.7 337 17.2 307 23.6 487 25.2 456 2.4 398 31.8 662 8.6617 0.0 515 15.3 899 0.2 835 0.0 666 0.8 1222 0.0 1129 0.0 863 0.0 16620.0 1527 0.0 1117 0.0 2258 0.0 2066 0.0 1446 0.0 3070 0.0 2794 0.0 18720.0 4172 0.0 3780 0.0 2424 0.0 5671 0.0 5114 0.0 3138 0.0 7708 0.0 69180.0 4063 0.0 10476 0.0 9358 0.0 5260 0.0 Average Particle 361.9 236.4336.7 Diameter (nm) Remarks Example Example Example

From the measurement results of the wet particle diameter distribution,it is revealed that good redispersibility is exhibited when the massratio of the nanoparticles to trehalose is within the range of from45:55 to 55:45 in the case where the nanocomposite particles wereprepared by using the nanoparticles having the average particle diameterof about 250 nm.

As a summary of the foregoing results, it is proved that theredispersibility in water of the nanocomposite particles of theinvention is irrelevant to the average particle diameter of thecontained nanoparticles, and the good redispersibility is exhibited whenthe mass ratio of the nanoparticles to disaccharide is within the rangeof from 45:55 to 55:45 as depending on the mass ratio.

Example 4

1.0 g of PLGA nanoparticles (average particle diameter: about 500 nm)prepared in the same manner as in Example 1-(1) were redispersed in 100ml of distilled water, and 1.0 g of trehalose was dissolved in thedispersion liquid to prepare a sample dispersion liquid. Nanocompositeparticles were prepared in the same manner as in Example 1 except forperforming the spray drying by using the thus-obtained sample dispersionliquid and varying the inlet temperature within the range of 60° C. to120° C.

A dry particle diameter distribution and a wet particle diameterdistribution were measured in the same manner as in Example 1. Resultsare shown in Table 9 and Table 10.

TABLE 9 Sample No. IV-1 IV-2 IV-3 IV-4 Nano-particles (g) 1.0 1.0 1.01.0 Trehalose (g) 1.0 1.0 1.0 1.0 Inlet Temperature (° C.) 60 70 80 90Dry Average Particle Diameter (μm) 6.15 6.33 3.49 2.46 Particle ParticleParticle Particle Diameter Volume Diameter Volume Diameter VolumeDiameter Volume (nm) (%) (nm) (%) (nm) (%) (nm) (%) Wet Particle 45 0.0115 0.0 135 0.0 80 0.0 Diameter 54 0.0 128 0.0 148 0.0 93 0.0Distribution 65 0.0 142 0.0 163 0.0 107 0.0 (immediately 79 0.0 157 0.0179 0.0 124 0.0 after) 95 0.0 174 0.0 197 0.0 143 0.0 114 0.0 193 0.0217 0.0 165 0.0 138 0.0 214 0.0 238 0.0 191 0.0 166 0.2 237 0.0 262 0.0220 0.2 200 0.5 263 0.6 288 0.3 254 0.9 242 1.2 292 2.6 317 1.8 294 2.5291 2.9 324 7.1 348 7.0 339 8.9 351 21.2 359 17.1 383 25.9 392 26.9 42438.5 398 31.4 421 39.6 453 35.4 511 22.0 441 30.2 463 22.4 523 18.0 6165.7 489 10.9 509 3.1 605 4.0 743 5.4 542 0.0 560 0.0 699 2.4 896 2.3 6010.0 615 0.0 807 0.8 1081 0.0 666 0.0 676 0.0 932 0.0 1303 0.0 738 0.0744 0.0 1077 0.0 1572 0.0 818 0.0 818 0.0 1244 0.0 1895 0.0 907 0.0 8990.0 1437 0.0 2286 0.0 1006 0.0 988 0.0 1660 0.0 2756 0.0 1115 0.0 10870.0 1918 0.0 3324 0.0 1236 0.0 1195 0.0 2216 0.0 Average Particle 458.4404.7 416.3 447.7 Diameter (nm) Remarks Example Example Example Example

TABLE 10 Sample No. IV-5 IV-6 IV-7 Nanoparticles (g) 1.0 1.0 1.0Trehalose (g) 1.0 1.0 1.0 Inlet Temperature (° C.) 100 110 120 DryAverage Particle Diameter (μm) 2.23 2.38 2.65 Particle Volume ParticleVolume Particle Volume Diameter (nm) (%) Diameter (nm) (%) Diameter (nm)(%) Wet Particle 86 0.0 5 0.0 15 0.0 Diameter Distribution 100 0.0 7 0.021 0.0 (immediately after) 117 0.0 11 0.0 30 0.0 136 0.0 17 0.0 42 0.0159 0.0 27 0.0 58 0.0 185 0.0 49 0.0 82 0.0 215 0.0 65 0.0 116 0.0 2500.3 102 0.0 163 0.0 291 1.3 158 0.3 230 0.3 339 7.0 246 18.0 324 9.2 39521.3 382 40.8 456 20.0 460 27.1 594 29.6 643 14.7 536 15.0 923 7.8 9054.9 624 10.0 1435 2.0 1275 1.2 727 12.3 2230 0.7 1796 2.0 846 5.5 34670.0 2530 6.1 985 0.1 5391 0.0 3564 14.4 1147 0.0 8381 0.0 5020 18.8 13360.0 13029 0.0 7071 8.4 1556 0.0 20257 0.1 9959 0.0 1811 0.0 31493 0.314028 0.0 2109 0.0 48961 0.3 19759 0.0 2456 0.0 76118 0.1 27831 0.0 28600.0 118340 0.0 39200 0.0 Average Particle 516.8 830.1 2517.1 Diameter(nm) Remarks Example Example Example

From Table 9 and Table 10, it is apparent that the dry average particlediameter increases with a reduction in inlet temperature. Also, it isrevealed that it is possible to obtain the nanocomposite particleshaving good redispersibility by maintaining the inlet temperature withinthe range of from 60° C. to 100° C. in the preparation. In the casewhere trehalose was used as disaccharide, alteration of trehalose isprevented by maintaining the inlet temperature to 100° C. or less,thereby making it possible to impart the good redispersibility of thenanocomposite particles.

Example 5

Nanocomposite particles were prepared in the same manner as in Example 4except for using lactose in place of trehalose, and a dry particlediameter distribution and a wet particle diameter distribution weremeasured. Results are shown in Table 11 and Table 12.

TABLE 11 Sample No. V-I V-2 V-3 V-4 Nano-particles (g) 1.0 1.0 1.0 1.0Lactose (g) 1.0 1.0 1.0 1.0 Inlet Temperature (° C.) 60 70 80 90 DryAverage Particle Diameter (μm) 5.69 2.37 2.37 1.88 Particle ParticleParticle Particle Diameter Volume Diameter Volume Diameter VolumeDiameter Volume (nm) (%) (nm) (%) (nm) (%) (nm) (%) Wet Particle 43 0.053 0.0 52 0.0 51 0.0 Diameter 52 0.0 63 0.0 62 0.0 61 0.0 Distribution62 0.0 74 0.0 74 0.0 72 0.0 (immediately 75 0.0 88 0.0 87 0.0 86 0.0after) 90 0.0 104 0.0 103 0.0 103 0.0 108 0.0 123 0.0 123 0.0 122 0.0130 0.1 146 0.0 146 0.0 146 0.0 156 0.5 173 0.1 173 0.0 174 0.0 188 1.2205 0.6 205 0.0 207 0.0 226 2.3 243 1.9 243 0.9 247 0.7 273 4.3 287 4.8288 10.0 294 4.6 328 14.2 341 20.0 342 33.1 350 28.3 395 28.7 403 36.8406 40.0 417 45.4 475 26.7 478 27.2 482 15.9 498 21.0 571 13.2 566 7.8571 0.0 593 0.0 687 6.2 671 0.8 678 0.0 707 0.0 827 2.5 795 0.0 804 0.0843 0.0 995 0.1 941 0.0 954 0.0 1004 0.0 1198 0.0 1115 0.0 1132 0.0 11970.0 1441 0.0 1321 0.0 1343 0.0 1427 0.0 1734 0.0 1565 0.0 1593 0.0 17010.0 2087 0.0 1854 0.0 1890 0.0 2027 0.0 2511 0.0 2196 0.0 2242 0.0 24160.0 3022 0.0 2602 0.0 2660 0.0 2880 0.0 Average 446.3 415.8 383.2 408.3Particle Diameter (nm) Remarks Example Example Example Example

TABLE 12 Sample No. V-5 V-6 V-7 Nanoparticles (g) 1.0 1.0 1.0 Lactose(g) 1.0 1.0 1.0 Inlet Temperature (° C.) 100 110 120 Dry AverageParticle Diameter (μm) 2.29 2.58 2.58 Particle Volume Particle VolumeParticle Volume Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)Wet Particle 18 0.0 14 0.0 10 0.0 Diameter Distribution 24 0.0 19 0.0 150.0 (immediately after) 33 0.0 97 0.0 21 0.0 45 0.0 37 0.0 31 0.0 61 0.051 0.0 46 0.0 82 0.0 70 0.0 68 0.0 111 0.0 96 0.0 99 0.0 151 0.1 132 0.0146 0.1 205 0.7 182 0.3 214 0.4 278 4.4 251 5.0 314 3.9 377 10.6 34616.6 461 9.5 511 20.3 476 19.7 677 13.3 693 27.8 656 9.4 994 14.6 94021.6 903 14.4 1460 11.5 1275 10.9 1244 23.6 2145 16.1 1729 3.5 1713 11.03150 21.2 2345 0.0 2359 0.0 4626 9.4 3180 0.0 3249 0.0 6793 0.0 4313 0.04474 0.0 9977 0.0 5849 0.0 6161 0.0 14652 0.0 7932 0.0 8485 0.0 215180.0 10757 0.0 11685 0.0 31602 0.0 14588 0.0 16091 0.0 46411 0.0 197840.0 22160 0.0 68160 0.0 Average Particle 752.8 838.0 1908.1 Diameter(nm) Remarks Example Example Example

From Table 11 and Table 12, it is apparent that the dry average particlediameter increases with a reduction in inlet temperature. Also, it isrevealed that it is possible to obtain the nanocomposite particleshaving good redispersibility by maintaining the inlet temperature withinthe range of from 60° C. to 90° C. in the preparation. In the case wherelactose was used as disaccharide, alteration of lactose is prevented bymaintaining the inlet temperature to 90° C. or less, thereby making itpossible to impart the good redispersibility of the nanocompositeparticles.

As a summary of the foregoing results, it is possible to prepare thenanocomposite particles exhibiting the good redispersibility when theinlet temperature of the spray drying machine in the spray drying iswithin the range of from 60° C. to 100° C.

Also, it is revealed that it is possible to achieve an aerodynamicparticle diameter distribution suitable for delivering the nanocompositeparticles of the invention to the alveoli when the inlet temperature is70° C. or more. Therefore, it is proved that, by maintaining the inlettemperature of the spray drying machine within the range of from 70° C.to 100° C. it is possible to prepare the nanocomposite particles havinggood characteristics as a pulmonary administration preparation in termsof the redispersibility and the aerodynamic particle diameterdistribution. Further, it is proved that better characteristics areobtained when the inlet temperature of the spray drying machine iswithin the range of from 80° C. to 900° C.

Comparative Example 1

1.0 g of PLGA nanoparticles (average particle diameter: about 250 nm)prepared in the same manner as in Example 3-(1) was redispersed in 100ml of distilled water, and 1.0 g of mannitol was dissolved in thedispersion liquid to prepare a sample dispersion liquid. Nanocompositeparticles were prepared in the same manner as in Example 1 except forusing the thus-obtained sample dispersion liquid, and a dry averageparticle diameter and a wet particle diameter distribution weremeasured, Results are shown in Table 13. Note that the measurementresults of Sample No. III-2 are also shown in Table 13 for the purposeof comparison.

TABLE 13 Sample No. VI Sample No. III-2 Nanoparticles (g) 1.0Nanoparticles (g) 1.0 Mannitol (g) 1.0 Trehalose (g) 1.0 Dry AverageParticle 2.47 Dry Average Particle 2.16 Diameter (μm) Diameter (μm) WetParticle Wet Particle Wet Particle Wet Particle Diameter DistributionDiameter Distribution Diameter Distribution Diameter Distribution(immediately after) (10 minutes after) (immediately after) (10 minutesafter) Particle Volume Particle Volume Particle Volume Particle VolumeDiameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%) Diameter (nm) (%)  3 0.0 3 0 9 0.0 14 0   5 0.0 5 0 12 0.0 18 0   7 0.0 7 0 16 0.0 23 0 11 0.0 11 0 22 0.0 30 0  16 0.0 16 0 30 0.0 39 0  25 0.0 24 0 41 0.0 500  37 0.0 37 0 55 0.0 65 0  55 0.0 55 0 74 0.0 85 0  83 1.2 82 1.5 1010.0 110 1.4  124 8.3 123 7.5 136 10.2 142 7.4  186 14.8 185 13.5 18432.8 185 17  279 9.5 277 10.4 249 37.4 239 23.7  419 1.8 415 2.9 33717.2 310 25.4  629 2.7 623 1.4 456 2.4 402 18.9  944 18.7 934 17.4 6170.0 522 6.2 1416 29.5 1401 30.7 835 0.0 676 0 2125 13.4 2102 14.7 11290.0 877 0 3188 0.0 3153 0 1527 0.0 1137 0 4784 0.0 4730 0 2066 0.0 14740 7178 0.0 7095 0 2974 0.0 1911 0 10770  0.0 10643 0 3780 0.0 2478 016159  0.0 15946 0 5114 0.0 3213 0 24246  0.0 23946 0 6918 0.0 4166 036380  0.0 35920 0 9358 0.0 5402 0 Average 968.9 Average 986.7 Average236.4 Average 287.3 Particle Particle Particle Particle DiameterDiameter Diameter Diameter (nm) (nm) (nm) (nm) Remarks ComparativeExample Remarks Example

From Table 13, it is apparent that, in the case where mannitol which isa sugar alcohol was used in place of trehalose which is disaccharide,the wet average particle diameter gives two peaks, and the nanoparticlesare not completely redispersed. Also, since no major change is observedwith the wet particle diameter distribution in the measurement of 10minutes after the water addition, it is proved that the nanoparticlesremain not completely redispersed.

Example 6

An aerodynamic particle diameter distribution of the nanocompositeparticles of each of Sample Nos. (III-1) to (III-3) obtained by Example3 was evaluated by using an Andersen type cascade impactor and employingthe following procedure.

(1) The measurement sample was vacuum dried for two hours in a vacuumdrier, and 30 mg of the measurement sample was weighed in a measurementcapsule.(2) By using the Andersen type cascade impactor (AN-200 manufactured byTokyo Dylec Corp.) and a dry powder inhaler (DPI, Jethaler manufacturedby Hitachi, Ltd.), suction was performed for 5 seconds at a flow rate of28.3 l/min.(3) A particle deposition amount on each of the stages was calculated bydissolving the deposited particles in chloroform and measuringabsorbance (wavelength: 475 mm) of RFP in the chloroform.(4) An in-capsule residual particle amount was calculated by measuring amass of the capsule again, and a particle release amount was calculatedfrom a difference with the charged amount.(5) An FPF (Fine Particle Fraction)(%) which is a proportion of a totalof particle masses deposited in the stages 3 to 7 (lower stages) to atotal particle mass was calculated.

Table 14 shows particle release efficiency ED (%), deposited particlemasses (mg) of stages 0 to 7, and FPF (%) of the samples. Also, theaerodynamic particle diameter distribution of Sample (III-2) is shown inFIG. 1.

TABLE 14 Sample No. III-1 III-2 III-3 Nanoparticles (g) 0.9 1.0 1.1Trehalose (g) 1.1 1.0 0.9 Charged Amount (mg) 30.2 30.3 30.2 ParticleRelease Amount (mg) 27.6 29.0 28.4 ED (%) 91.4 95.7 94.0 Mass ofDeposited 0 0.60050 0.47062 0.36243 Particles in Each 1 0.44141 0.542290.45916 of Stages (mg) 2 1.38902 1.71840 4.79857 3 3.03600 2.788571.58612 4 2.95989 1.84334 2.52452 5 1.04172 0.62610 0.93068 6 0.167850.11715 0.15967 7 0.00000 0.00000 0.00000 FPF (%) 23.9 17.7 17.2

From Table 14, it is apparent that each of Samples (III-1) to (III-3)shows good particle release efficiency.

The FPF is a value suitably used for evaluating the degree of deliveryto the alveoli, and the larger the FPF, the more excellent the deliveryto the alveoli becomes. It is apparent that each of Samples (III-1) to(III-3) shows a good FPF. That is, it is apparent that Samples (III-1)to (III-3) have a large proportion of particles having an aerodynamicparticle diameter of 0.13 to 4.7 μm that is suitable for delivery toalveoli and exhibit a favorable flying property.

Therefore, according to the nanocomposite particles of the invention,which include nanoparticles containing a drug to delivered and abiodegradable polymer, and a sugar material, and in which the sugarmaterial is disaccharide, and the mass ratio of the nanoparticles to thedisaccharide is within the range of from 40:60 to 60:40, it is possibleto provide nanocomposite particles having good solubility in water andgood redispersibility when brought into contact with water.

1. Nanocomposite particles comprising a sugar material and nanoparticlesincluding a drug to be delivered and a biodegradable polymer, whereinthe sugar material is disaccharide; and a mass ratio of thenanoparticles to the disaccharide is within a range of from 40:60 to60:40.
 2. The nanocomposite particles according to claim 1, wherein themass ratio of the nanoparticles to the disaccharide is within a range offrom 45:55 to 55:45.
 3. The nanocomposite particles according to claim1, wherein the biodegradable polymer is a biodegradable polymercomprising at least one selected from the group consisting of polylacticacid, polyglycolic acid, poly(lactic acid-glycolic acid), andpolycyanoacrylate.
 4. The nanocomposite particles according to claim 1,wherein the disaccharide is at least one selected from the groupconsisting of sucrose, maltose, lactose, trehalose, and cellobiose. 5.The nanocomposite particles according to claim 1, wherein thebiodegradable polymer is a biodegradable polymer comprising at least oneselected from the group consisting of polylactic acid, polyglycolicacid, poly(lactic acid-glycolic acid), and polycyanoacrylate, and thedisaccharide is at least one selected from the group consisting ofsucrose, maltose, lactose, trehalose, and cellobiose.
 6. Thenanocomposite particles according to claim 1, wherein the biodegradablepolymer is a biodegradable polymer comprising poly(lactic acid-glycolicacid) and the disaccharide is lactose and/or trehalose.
 7. Thenanocomposite particles according to claim 1, wherein the nanocompositeparticles are obtained by spray drying a solution comprising thenanoparticles and the disaccharide.
 8. The nanocomposite particlesaccording to claim 7, wherein an inlet temperature of a spray dryingmachine in the spray drying is within a range of from 60° C. to 100° C.9. The nanocomposites particle according to claim 7, wherein an inlettemperature of the spray drying machine in the spray drying is within arange of from 60° C. to 90° C.
 10. A production method for thenanocomposite particles according to claim 1, the method comprisingspray drying a solution comprising nanoparticles comprising a drug to bedelivered and disaccharide.
 11. The production method for thenanocomposite particles according to claim 10, wherein an inlettemperature of a spray drying machine in the spray drying is within arange of from 60° C. to 100° C.
 12. The production method for thenanocomposite particles according to claim 10, wherein an inlettemperature of the spray drying machine in the spray drying is within arange of from 60° C. to 90° C.